How does Hyperbaric Oxygen Therapy benefit the older adult patient?

Hyperbaric Oxygen Therapy: A Brief History and Review of its Benefits and Indications for the Older Adult Patient

 www.managedhealthcareconnect.com/article/hyperbaric-oxygen-therapy-brief-history-and-review-its-benefits-and-indications-older-adult

Affiliations: ¹Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Maryland School of Medicine, Baltimore, MD^{; 2}University of Maryland Medical Center and GRECC, Baltimore VA Medical Center, Baltimore, MD

Abstract: Hyperbaric oxygen (HBO₂) therapy has long been used to treat decompression sickness, but more recently has been explored as a primary or adjunctive therapy for a number of injuries and medical conditions, many of which commonly affect the aging adult population. Its potential benefit in conditions such as acute traumatic ischemia, necrotizing soft tissue injuries, nonhealing ulcers, and osteoradionecrosis are of particular interest. Yet, despite evidence for its benefit in decompression sickness and air embolism, there are few randomized controlled clinical trials documenting the effects of HBO₂ therapy for the range of other conditions for which it has been reported to have benefit. Much research remains to be done regarding the advantages and efficacy of HBO₂ therapy, so that clinicians are enabled to develop treatment plans for their elderly patients that incorporate all possible beneficial therapies. This article provides a brief overview of HBO₂ therapy, reviewing its history, potential mechanism of action, indications in the older adult population, safety and side effects, and its potential role in nursing home care.

Hyperbaric oxygen (HBO₂) therapy has been used for some time with success in the treatment of decompression sickness, but more recently has been explored as a primary or adjunctive therapy for a number of injuries and medical conditions, many of which commonly affect the aging adult population. The Centers for Medicare & Medicaid Services (CMS) reimburses for HBO₂ for the treatment of decompression sickness; several acute conditions, including carbon monoxide toxicity, clostridial myonecrosis (also known as gas gangrene), and crush injuries; and for several chronic conditions, including refractory osteomyelitis, radionecrosis, and select diabetic wounds.¹ Particularly of interest for older adult patients is the application of HBO₂ in cases of acute traumatic ischemia secondary to motor vehicle accidents or falls; necrotizing soft tissue injuries, especially those associated with comorbid conditions (eg, immunosuppression, diabetes, renal failure, peripheral arterial disease); nonhealing ulcers in bed-bound patients with malnutrition; osteoradionecrosis resulting from radiation therapy; and air embolism resulting from procedures such as cardiac catheterization and central line or port placements for chemotherapy, which are used with increasing frequency in this population. This article reviews the history of HBO₂ and its applications across a range of conditions common among the elderly population. It also examines the use of this therapy in skilled nursing facilities (SNFs), for which there is currently a paucity of information.

Overview of Hyperbaric Oxygen Therapy

The term hyperbaric literally means higher pressure (hyper means over, above, or beyond; baric means of or concerned with weight, especially that of the atmosphere as indicated by barometric pressure).² According to the Undersea and Hyperbaric Medical Society (UHMS), HBO₂ therapy involves breathing 100% oxygen while within a treatment chamber that has been pressurized to a pressure higher than sea level (ie, >1.0 atmosphere absolute [ATA]). This type of therapy has various potential mechanisms of action, the most important of which may be its ability to increase partial pressure of oxygen in the tissues of the body to a degree several times greater than that which can be achieved by breathing pure oxygen at a normal atmospheric pressure.³ The increased atmospheric pressure also increases the amount of oxygen in blood plasma, which has greater bioavailability to the tissues than does oxygen in hemoglobin. Breathing or exposing parts of the body to 100% oxygen alone does not constitute HBO₂ therapy; the oxygen must be received via inhalation within a pressurized chamber, typically pressurized to 1.4 ATA or higher.³

HBO₂ therapy can be delivered in one of three chamber types: high-pressure multiplace, high-pressure monoplace, or low-pressure monoplace. The most commonly used of these in medical settings are the high-pressure chambers, which are designed to hold either one person (ie, monoplace) or multiple people (ie, multiplace) at one time. In monoplace chambers, the entire chamber is pressurized with 100% oxygen and a single patient breathes the oxygenated air directly, whereas in multiplace chambers, several people sit within a chamber that is pressurized with compressed air and breath pure oxygen via tightly fastened masks, hoods, or endotracheal tubes. Multiplace chambers enable a higher volume of persons to receive treatment and are adaptable for more critically ill patients, as attendants may be present in the chamber during therapy to address patient complications or concerns. Alternatively, monoplace chambers are often found in smaller facilities and chronic wound treatment centers, and allow for more individualized therapy.

Most chambers are designed to operate at a pressure in the range of 2.0 to 2.5 ATA. Newer low-pressure monoplace chambers operate in the 1.2 to 1.3 ATA pressure range. These chambers are more frequently used in homes and spas, and are also employed to improve postoperative recovery from plastic surgery. Low-pressure monoplace chambers tend to be attractive in situations that require portability, lower cost, and increased availability. These chambers are relatively new and differences in therapeutic benefits compared with their high-pressure counterparts have not yet been researched; however, improvement is still seen in tissue oxygen delivery with a low-pressure unit—even though it might not be to the same degree as seen with high-pressure units.⁴

History of Hyperbaric Oxygen Therapy  

HBO₂ therapy has been described as a new application of an older, more established technology.³ Although the details are not completely clear, British physician Nathaniel Henshaw was reportedly the first person to use compressed air in a chamber called a domicilium to achieve an HBO₂ environment.⁴ While we associate this form of treatment as a modern advancement, his pioneer work dates back to 1662. Around this time, Robert Boyle, an Irish chemist, physicist, and inventor, stated that the pressure and volume of a gas have an inverse relationship when temperature is held constant.⁵ Boyle’s law formed the basis for many aspects of HBO₂ therapy, including the slight increase in the ambient temperature within the chamber during treatment sessions.

The two centuries that followed saw new reports of the benefits of using increased pressure for oxygenation, and by 1877 hyperbaric chambers had been used for a wide range of conditions, despite a general lack of scientific understanding or evidence about their mechanism of action or efficacy.⁵ These early chambers used compressed air, not oxygen, based on concerns about oxygen toxicity.^5-7 It was not until 1917 that German inventors Bernhard and Heinrich Dräger applied pressurized oxygen to successfully treat decompression illness from diving accidents.⁸

The first hyperbaric chamber in the United States was built in New York in 1861 by neurologist James Leonard Corning.⁹ Corning’s interest in HBO₂ therapy stemmed from witnessing severe decompression illness among the Hudson Tunnel site workers, who would often experience severe muscle pain and paralysis after working below water level all day. He used his chamber to treat such cases and a broader range of nondecompression-related nervous system disorders; however, treatments for the latter conditions failed to show much success.^9,10 Subsequently, the use of these chambers to treat conditions other than decompression illness was largely discontinued until 1921, when Kansas-based physician Orval J. Cunningham built a hyperbaric chamber in Kansas City.¹⁰ Cunningham built the chamber after observing that morbidity and mortality rates from the “Spanish influenza” pandemic were greater in higher elevations than in coastal areas, which he attributed to the barometric pressure. He observed some success with this therapy, and it has been suggested that a tragic event only served to further validate his beliefs in this treatment. One night, a mechanical failure in his chamber’s air compressor caused the pressure to rapidly decrease to normal atmospheric levels, killing all of its occupants. Not understanding the true mechanism behind his patients’ deaths, Cunningham surmised that the HBO₂ therapy had kept them alive and that they could not live in an environment without it.¹⁰ He went on to open the world’s largest HBO₂ chamber along the shores of Lake Erie in Cleveland, Ohio, in 1928.¹¹ This million-dollar, 900-ton sphere measured 64 feet in diameter, was 5 stories tall, and was equipped with 12 bedrooms on each floor. The structure was known as the Cunningham Sanitarium and was considered the first “attempt in human history to house people in such a unique structure.”^4,12 Scarce information is available regarding the treatments that the facility actually provided; however, historical records indicate that the facility treated patients with a variety of illnesses, but especially focused on diabetes.¹³ Cunningham believed that many illnesses, including diabetes and cancer, are caused by anaerobic organisms that can be killed by exposure to oxygen¹⁴; however, he drew criticism from the American Medical Association because he failed to document his claims regarding the effectiveness of HBO₂ despite numerous requests to do so.¹⁵ Subsequently, the chamber was in use for only a short period and dismantled in 1937 for scrap metal.¹⁵ That same year, Albert Behnke and Louis Shaw built on the Drägers’ work for decompression illness and used oxygen in place of compressed air.¹⁵ Their work led to use of the first nitrogen-oxygen mixtures and hyperbaric treatment being tailored to the severity of the injury.^10,15

More mainstream interest in HBO₂ to treat medical conditions beyond decompression illness was not renewed until 1956, when Dutch cardiac surgeon Ite Boerema reported on the use of HBO₂ as an aid in cardiopulmonary surgery.¹⁰ Thereafter, more promising reports on the use of HBO₂ surfaced, including one by Boerema’s colleague, Willem Brummelkamp, who reported in 1961 that anaerobic infections were inhibited by HBO₂ therapy.¹⁰ Since then, HBO₂ has been used in the treatment of numerous medical conditions, including carbon monoxide poisoning, infections, wound healing, and trauma.¹⁶ The precise mechanism of action of HBO₂ is still not fully understood, but several factors appear to contribute to its benefits.

Understanding the Proposed Mechanism of Action of Hyperbaric Oxygen Therapy

Oxygen is necessary to provide energy and to support cellular respiration. Injury or disease diminishes the body’s ability to transport oxygen to the tissues, yet infections and tissue healing increase demand in the tissues for oxygen. Conditions such as hemolytic anemia, exposure to toxins, and hemorrhage can affect the body’s ability to transport oxygen, whereas edema, decreased perfusion, and microthrombosis can affect the distance that oxygen must travel from the capillaries to the cells.

The majority of the oxygen transported in the blood is carried on hemoglobin; however, some oxygen is carried in the plasma. Henry’s Law states that the relationship between the volume of gas dissolved in a liquid or tissue and the partial pressure of that gas is proportional.⁵ Therefore, based on this law, increasing atmospheric pressure will cause more oxygen to dissolve in the plasma, thereby maximizing tissue oxygenation.

Furthermore, increasing the concentration of a gas within a fluid increases its partial pressure within the fluid.¹⁶ The increased partial pressure increases the driving force for diffusion and thereby increases its diffusion distance, as defined by Fick’s Law. Oxygen dissolved in plasma is most bioavailable to the tissues because the increased concentration of oxygen proportionally increases the partial pressure of oxygen in arterial blood, and more oxygen can be delivered deeper into the tissues. Increasing the pressure from 1.0 ATA to between 2.0 and 2.5 ATA, the oxygen dissolved in plasma increases approximately three-fold if the patient is breathing room air. When the inhaled oxygen concentration is increased to 100% under pressure, the plasma oxygen concentration increases by almost 17-fold. In theory, with 100% oxygen at 2.5 ATA, enough oxygen can be dissolved in plasma to meet the normal requirements of the body at rest without the need for hemoglobin.¹⁶

Oxygen delivery is also affected by perfusion and by variable degrees of vasodilation and vasoconstriction within different tissues. Arterioles and venules typically vasoconstrict at high oxygen tensions, most likely due to a decrease in the availability of endogenous nitric oxide. This is a protective mechanism in response to hyperoxia in normal tissues during HBO₂, and it acts to protect tissues from increased oxidative damage. Decrease in blood flow is compensated for by the increased partial pressure of the oxygen in plasma, so overall tissue oxygenation during HBO₂ remains high, and microvascular blood flow in ischemic and postischemic tissues actually improves, as the vasoconstrictive mechanisms in these tissues are impaired.^5,17 Further, vasoconstriction has benefits in the case of crush injuries, compartment syndromes, and burns, where posttraumatic edema is reduced as a result of diminished blood flow.^5,18 Additionally, carbon dioxide build-up in these areas contributes to vasodilation; in fact, carbon dioxide is a more potent vasodilator than oxygen is a vasoconstrictor. This vasodilation and enhanced oxygenation of injured tissues helps to preserve adenosine triphosphate levels and to inhibit swelling and edema formation by maintaining energy-dependent cellular functions.

In addition to its effects on cellular function, HBO₂ impacts the immune system. Oxygen has an antimicrobial effect, especially in anaerobic infections. The oxygen-derived free radicals that are formed in the reperfusion state have bactericidal effects. Likewise, HBO₂ stimulates phagocytosis within affected tissues. HBO₂ has been shown to have beneficial effects on fibroblast activity and angiogenesis; to enhance the efficacy of leukocytes; to suppresses bacteria; to increase the efficacy of antibiotics; and to stimulate granulocytes’ production of endogenous antimicrobial agents.^19-22

Indications of Hyperbaric Oxygen Therapy for Older Adults

To date, there are few randomized, controlled clinical trials on the use of HBO₂. Many of its widely accepted uses are based on experimental animal models and clinical experience.²² The UHMS performs an evidence-based medicine review of the available literature and publishes a report with a list of indications every 3 years, which are used by CMS and other third-party insurance agencies to determine reimbursement for HBO₂ services in the United States²²; the latest report was published in April 2014 (www.bestpub.com/hbot). To follow is a brief overview of key indications of HBO₂ that are specific to the aging and elderly adult populations. A complete listing of approved indications from CMS and the UHMS are provided in Table 1 and Table 2, respectively.^1,22

Necrotizing Soft Tissue Infections

Necrotizing fasciitis, also known as flesh-eating disease, is a bacterial infection of the deep fascia with secondary involvement in the underlying skin and vasculature. It progresses rapidly, and morality rates associated with the disease have been noted to range from 30% to 75%.²³ It primarily affects immunocompromised individuals, infants, and the elderly. The presence of several systemic illnesses increases the risk of developing necrotizing fasciitis, including diabetes mellitus, peripheral vascular disease, malignancy, and atherosclerosis, all of which are common among the elderly, including those residing in nursing homes.²⁴ Primary treatment of a necrotizing soft tissue infection is typically intravenous antibiotics and surgical debridement. CMS also reimburses for HBO₂ as a treatment for progressive necrotizing infections.¹

It has been reported that adjunctive HBO₂ may decrease mortality and limit the extent of debridement necessary in treating necrotizing fasciitis. Although no randomized, controlled trials in humans have been conducted, a retrospective review of a nationwide database from Singapore (Nationwide Inpatient Sample) identified 45,913 cases of necrotizing soft-tissue infection and reported a statistically significant reduction in mortality among patients treated with HBO₂ versus those who did not receive this therapy (n=405; 4.5% vs 9.4%, respectively; P=.001).²⁵ After adjusting for predictors and confounders, patients who received HBO₂ had a statistically significantly lower risk of death (odds ratio, 0.49; 95% confidence interval, 0.29-0.83), higher hospitalization cost ($52,205 vs $45,464; P=.02), and longer hospital stays (14.3 days vs 10.7 days; P<.001). However, the researchers concluded that, despite the high cost and long hospitalization associated with the therapy, the statistically significant reduction in mortality supported its use in necrotizing infections.²⁵

Smaller retrospective studies have reported conflicting results. HBO₂ has been advocated for use in treating severe invasive infections. When used to treat acute infections, HBO₂ should be implemented early with two to three daily 90-minute HBO₂ sessions at 3.0 ATA.²² 

Acute Traumatic or Thermal Injuries

HBO₂ is recommended as adjunctive therapy for a range of acute traumatic and ischemic syndromes, including crush injuries, compartment syndromes, and situations of vascular compromise²²; however, CMS only reimburses for crush injuries and suturing of severed limbs.¹ Benefits of HBO₂ in the setting of acute traumatic or thermal injuries may be due to a combination of increased tissue oxygenation, reduced edema through hyperoxia-induced vasospasm, protection from reperfusion injury and secondary ischemia, and antimicrobial effects.

In a randomized, double-blinded, placebo-controlled clinical trial, 36 patients with crush injuries were assigned to receive either treatment with HBO₂ (twice-daily sessions of 100% oxygen at 2.5 ATA for 90 minutes over 6 days) or placebo (twice-daily sessions of 21% oxygen at 1.1 ATA for 90 minutes over 6 days) within 24 hours of surgery.²⁶ Analysis of patient groups matched for age and severity of injury showed that in the subgroup of patients older than 40 years with grade 3 soft-tissue injuries, wound healing was obtained for seven patients (87.5%) in the HBO₂ group versus three patients (30%) in the placebo group (P<.05). This study established HBO₂ as a useful adjunct in the management of severe crush limb injuries.²⁶

Nonhealing Ulcers, Skin Grafts, and Wound Healing

HBO₂ is often used as an adjunctive therapy in the treatment of nonhealing wounds, compromised skin grafts, and other injuries; however, there are no randomized, controlled trials documenting efficacy for these indications. Most studies are observational and the few available trials are limited by small sample size and low quality.²⁷

A systematic review of the literature to determine whether HBO₂ is effective as adjunct therapy for hypoxic wounds suggested that it may be a beneficial adjunctive treatment for chronic nonhealing diabetic wounds (specifically, stage 3C foot ulcers), compromised skin grafts, osteoradionecrosis, soft-tissue radionecrosis, and gas gangrene, compared with standard wound care alone,²⁷ and it is reimbursable by CMS for all of these indications.¹ Therapy for such nonhealing wounds generally consists of daily sessions of 1.5 to 2 hours of oxygen or air at pressures of 2.5 to 3.0 ATA for 20 to 40 days.²⁷ It is important to note that CMS does not reimburse for HBO₂ as a treatment for cutaneous, decubitus, and stasis ulcers.¹

Radiation Injury

An irradiated tissue develops fibroatrophic changes with decreased vascularity, impaired cellular proliferation, and local hypoxia that can persist long after radiation therapy has ceased. Subsequent injury (eg, dental extraction) or surgical manipulation may lead to soft-tissue radionecrosis and osteoradionecrosis, manifested by edema, ulceration, poor wound healing, and infection.

A literature review revealed that HBO₂ may reduce soft-tissue radionecrosis and improve reconstructive outcomes in patients who have received chest, pelvic, perineal, or extremity irradiation; however, the available data are conflicting, and the benefit of HBO₂ to prevent or treat established osteoradionecrosis of the jaw in irradiated patients with head and neck cancer is uncertain.²⁸Further studies need to be conducted to determine the benefits of HBO₂ in preventing radionecrosis before it can be recommended for use in these cases. Although the UHMS advocates for HBO₂ as a treatment for delayed radiation injuries,²²CMS does not reimburse for HBO₂ when used for this purpose.¹

Safety, Efficacy, and Side Effects of HBO₂

As previously noted, there is strong evidence for the use of HBO₂ in decompression sickness and air embolism; however, much research remains to be done regarding the safety and efficacy of HBO₂ therapy for other medical conditions. Currently, there are few randomized controlled clinical trials documenting its effects in humans. Nevertheless, clinical experience reports have found HBO₂ to be relatively safe. The most commonly noted side effect is middle ear barotrauma, with a reported incidence of approximately 2%.²⁹ Sinus squeeze, claustrophobia, and progressive myopia have also been reported; the latter is a result of increased pressure and hyperoxia from long-term use, but it is reversible.^5,29 Pulmonary barotrauma with or without associated air embolism may be a rare effect of decompression after therapy; patients at highest risk for this are those with an airway obstruction. In patients with a history of spontaneous pneumothorax, careful consideration of potential risk versus benefit should be taken before deciding to start HBO₂.²⁹

HBO₂ in Skilled Nursing Facilities

Currently, HBO₂ therapy is an outpatient therapy that is typically found in outpatient departments of hospitals and medical centers. In 2009, fewer than 1% of US nursing homes had HBO₂ chambers, compared with approximately 20% of hospitals.³⁰ The utilization rate continues to be low in SNFs because there is no specific reimbursement for HBO₂ therapy when provided as an inpatient treatment; thus, patients generally have to be transported to outpatient facilities to receive HBO₂ therapy, posing numerous logistical challenges (eg, transportation, comfort of particularly frail elders). Subsequently, not all residents who might benefit from the treatment will receive it. Furthermore, although HBO₂ has been used to treat a wide variety of wounds, CMS only reimburses this treatment for diabetic stage 3C ulcers, not pressure wounds, the latter of which are more commonly encountered in SNFs. In addition, many wound-healing plans require 30 to 40 HBO₂ therapies administered 5 days per week, compounding the aforementioned logistical issues.³¹

Despite the current underutilization of HBO₂ therapy in SNF settings, these environments may be ideally suited to provide this emerging therapy. As in the hospital setting, SNFs are staffed with healthcare professionals who can be trained to provide HBO₂ therapy. Numerous institutions throughout the United States provide training programs, including International ATMO (www.hyperbaricmedicine.com) in San Antonio, Texas.³⁰ Even if SNFs are unlikely to adopt HBO₂ therapy as part of their own service offerings in the near future, it is important for long-term care providers to be familiar with this therapy to ensure it is not overlooked for eligible patients, particularly as reimbursable indications continue to expand.

Conclusion

Many indications for HBO₂ therapy have been proven in well-controlled studies, while others have not received careful review or have been evaluated using less than optimal research methodology with inconclusive data available upon which to form clinical decisions; thus, this is an area where high-quality, randomized, controlled clinical trials are desperately needed. Nevertheless, as our population continues to age, it is likely that we will see a greater number of conditions that may benefit from HBO₂ therapy, particularly because its uses are continuing to be explored in clinical settings. Therefore, it behooves all healthcare providers to be familiar with this treatment option, including those caring for geriatric patients in the long-term care setting, to ensure all eligible patients are at least made aware of this treatment option when appropriate.

References

1.     Centers for Medicare & Medicaid Services. Manual section number 20.29: hyperbaric oxygen therapy. In: Medicare National Coverage Determinations Manual.
   Version Number 3. US Department of Health and Human Services; 2006.
2.     The Free Dictionary by Farlex. www.thefreedictionary.com. Accessed April 24, 2014.
3.     Indications for hyperbaric oxygen therapy. Undersea and Hyperbaric Medical Society. Accessed April 24, 2014.
4.     Edwards ML. Hyperbaric oxygen therapy. Part 1: history and principles. J Vet Emerg Crit Care. 2010;20(3):284-288.
5.     Gill AL, Bell CNA. Hyperbaric oxygen: its uses, mechanisms of action and outcomes. QJM: An International Journal of Medicine. 2004;97(7):385-395.
6.     Lorrain-Smith J. The pathological effects due to increase of oxygen tension in the air breathed. J Physiol. 1889;24:19-35.
7.     Yarbrough OD, Behnke AR. Treatment of compressed air illness utilizing oxygen. J Indust Hyg Toxicol. 1939;21:213-218.
8.     Diving equipment and systems. Dräger. www.draeger.net/HK/en/products/diving. Accessed May 14, 2014.
9.     Stewart J Jr. James Leonard Corning 1860. In: Exploring the History of Hyperbaric Chambers, Atmospheric Diving Suits and Manned Submersibles: The Scientists and Machinery. Bloomington, IN: Xlibris; 2011:68. http://bit.ly/1o6LZhU. Accessed May 14, 2014.
10.   Clark D. History of hyperbaric therapy. In: Neuman TS, Thom SR, eds. Physiology and Medicine of Hyperbaric Oxygen Therapy. 1st ed. Philadelphia, PA: Saunders; 2008:3-18.
11.   Hyperbaric options. History of hyperbaric medicine and therapy. http://hyperbaricoptions.com/education/hbot_history.php. Accessed May 14, 2014.
12.   Monster steel ball forms air cure hospital. Lakeside Press. www.lakesidepress.com/pulmonary/hyperbaric/steelball.htm. Accessed April 24, 2014.
13.   Cunningham Sanitarium – The Encyclopedia of Cleveland History. Case Western Reserve University. http://ech.case.edu/cgi/article.pl?id=CS6. Accessed May 14, 2014.
14.   Choffin M. The Cunningham Sanitarium. Cleveland Historical website. http://clevelandhistorical.org/items/show/378#.U3zgU61dWGl. Accessed May 14, 2014.
15.   America 1860 – 1940. London Diving Chamber. www.londondivingchamber.co.uk/index.php?id=history&page=7. Accesed May 14, 2014.
16.   Jain KK. Indications, contra-indications, and complications of hyperbaric oxygen therapy. In: Textbook of Hyperbaric Medicine. 4th ed. Kirkland, WA: Hogrefe and Huber Publishers; 2004:98-107.
17.   Zamboni WA, Roth AC, Russell RC, Graham B, Suchy H, Kucan JO. Morphological analysis of the microcirculation during reperfusion of ischaemic skeletal muscle and the effect of hyperbaric oxygen. Plast Reconstr Surg. 1993;91(6):1110-1123.
18.   Wattel F, Mathieu D, Neviere R, Bocquillon N. Hyperbaric therapy: acute peripheral ischaemia and compartment syndrome: a role for hyperbaric oxygenation. Anaesthesia. 1998;53(suppl 2):63-65.
19.   Tompach PC, Lew D, Stoll JL. Cell response to hyperbaric oxygen treatment. Int J Oral Maxillofac Surg. 1997;26(2):82-86.
20.   Muhonen A, Haaparanta M, Gronroos T, et al. Osteoblastic activity and neoangiogenesis in distracted bone of irradiated rabbit mandible with or without hyperbaric oxygen treatment. Int J Oral Maxillofac Surg. 2004;33(2):173-178.
21.   Thom SR. Effects of hyperoxia on neutrophil adhesion. Undersea Hyperb Med. 2004;31(1):123-131.
22.   Gesell LB, ed. Hyperbaric Oxygen Therapy Indications. 12th ed. Durham, NC: Undersea and Hyperbaric Medical Society; 2008:7-196.
23.   Hampson NB, ed. Hyperbaric oxygen therapy: 1999 committee report. Kensington MD: Undersea and Hyperbaric Medical Society, 1999.
24.   DeBoer SL, Zeglin D. Fasciitis even with optimal treatment, the mortality rate is 40%. Am J Nurs. 2001;101(4):37-38. www.nursingcenter.com/lnc/journalarticle?Article_ID=482116. Accessed May 27, 2014.
25.   Soh CR, Pietrobon R, Freiberger JJ, et al. Hyperbaric oxygen therapy in necrotising soft tissue infections: a study of patients in the United States Nationwide Inpatient Sample. Intensive Care Med. 2012;38(7):1143-1151.
26.   Bouachour G, Cronier P, Gouello JP, Toulemonde JL, Talha A, Alquier P. Hyperbaric oxygen therapy in the management of crush injuries: a randomized double-blind placebo-controlled clinical trial. J Trauma. 1996;41(2):333-339.
27.   Thom SR. Hyperbaric oxygen: its mechanisms and efficacy. Plast Reconstr Surg. 2011;127(suppl 1):131S-141S.
28.   Spiegelberg L, Djasim UM, van Neck HW, Wolvius EB, van der Wal KG. Hyperbaric oxygen therapy in the management of radiation-induced injury in the head and neck region: a review of the literature. J Oral Maxillofac Surg. 2010;68(8):1732-1739.
29.   Side effects. Undersea and Hyperbaric Medical Society. Accessed April 24, 2014.
30.   Finn MP. Nursing home wound care: the case for hyperbaric medicine. www.ltlmagazine.com/article/nursing-home-wound-care-case-hyperbaric-medi…. Published April 30, 2009. Accessed May 27, 2014.
31.   Hyperbaric oxygen therapy. Northern Nevada Medical Center. www.nnmc.com/hospital-services/wound-care/hyperbaric-oxygen-therapy. Accessed May 27, 2014.